Lead poisoning, particularly in children, remains a major health problem in the United States today. Nearly 19% of the children in a recent series of screening programs from 1969-1971 had blood levels of lead of 60 microns/100 ml or higher, amounts that are generally accepted by physicians as beig severe enough to require treatment. Lead intoxication is known to affect the erythropoietic system, producing anemia. One possible mechanism for the production of anemia is inhibition of heme biosynthesis in erythropoietic tissue. A dialyzable factor, identified as a polyglutamated folic acid derivative (pteroylpolyglutamate), has been discovered that protects against lead inhibition of uroporphyrinogen I synthetase, an enzymatic step of the heme biosynthetic pathway. This pteroylpolyglutamate has also been found to be an activator of the enzyme which indicates that such a pteridine derivative functions as a coenzyme for this enzymatic reaction. The objectives of the proposed research are to elucidate the role that pteroylpolyglutamates serve in the regulation of inhibition of uroporphyrinogen synthetase activity by lead and other inhibitors to learn how drugs, hormones and pteridine derivatives regulate this enzyme and the synthesis of heme, to extend these studies to extrahepatic tissues, such as the brain, kidney, bone marrow and endocrine system, and to the neonate. The results of these investigations will provide valuable information on the mechanism of the conversion of porphobilinogen to uroporphyrinogen and the synthesis of heme, and its regulation by lead and other inhibitors. This information will contribute to our knowledge of lead and drug toxicity and its treatment.